Recent evidence has implicated small RNA transcripts known as microRNAs in at least certain types of cancer. MicroRNAs (miRNAs) are small, non-coding RNA transcripts that play a critical role in silencing patterns of gene expression. The target specificity of individual microRNAs may be determined by a stretch of 6 nucleotides located from 2 through 7 of the mature microRNA transcript. These nucleotides, known as the “seed sequence” promote the binding of individual microRNAs to the 3′ untranslated region of mRNA transcripts. The resulting duplex is incorporated into the RNA-induced silencing complex (RISC), leading to translational repression often as a result of mRNA degradation. Because sequences complementary to an individual microRNA seed can be found in many different 3′UTRs, a single microRNA can target hundreds of different mRNAs across and within multiple pathways.
One exemplary type of cancer in which miRNAs may play a role is ovarian cancer. Platinum-based chemotherapy is standard of care for all women newly diagnosed with an epithelial ovarian cancer. These drugs include carboplatin, cisplatin, oxaloplatin and may be used singly or in combination with other agents including paclitaxel, doxetaxel, gemcitabine, liposomal doxorubicin, bevacizumab, cyclophosphamide or topotecan. Despite excellent response rates (>80%), there are a number of issues associated with the use of platinum-based agents to treat ovarian cancer. First, not all ovarian cancers respond well to these treatments. Approximately 20% of women with advanced ovarian cancers demonstrate de novo resistance to these agents. Second, small (microscopic) volume disease persists after standard of care treatment even in those women who achieve a complete clinical response, as judged by imaging, serum levels of tumor marker and physical examination, for example. These implants eventually activate to repopulate disease recurrences. Third, recurrent ovarian cancer eventually becomes resistant to platinum-based therapy. Because platinum is currently by far the most effective agent used to treat ovarian cancer, nearly all women with recurrent disease are treated with platinum either alone or in combination with some other agent. However, with continued use, almost all ovarian cancers become resistant to its cytotoxic activity. Ultimately, nearly all (>90%) of women with ovarian cancer die from a platinum-resistant recurrence of their disease. Although higher doses of platinum agents have been shown to induce better responses, their use is limited because of the toxicity associated with dose escalation. Toxicities are also a problem for women being treated with current standard of care regimens. As many as 40% of women being treated for ovarian cancer with current regimens experience problems with severe neutropenia, neuropathy and/or kidney damage that require dose reductions, further limiting the ability of clinicians to utilize dose intense or dose escalation strategies for the treatment of ovarian and other human cancers with platinum agents. Other side effects that can require dose reductions that limit efficacy include neutropenia, anemia, renal dysfunction, poor appetite, myalgias, fatigue, nausea and vomiting. In situations where these side effects limit the use of platinum agents or where platinum agents are no longer effective, a number of phase II clinical trials have established the efficacy of agents that are used by clinicians to manage this disease. These agents include liposomal docetaxel, etoposide, gemcitabine, liposomal doxorubicin, topotecan, bevacizumab, altretamine capecitabine, cyclophosphamide, irinotecan, malphalan, oxaliplatin, pemetrexed and vinolrelbine. (1-7). The efficacy of each of these agents has been tested in phase II clinical trials that support their use in the context of platinum-resistant ovarian cancer. In addition to the dose regimens documented formally as part of phase II clinical trials, more recent data indicates that alternative dosing regimens of these agents alone or in combination may enhance the efficacy. For example, recent evidence suggests that the combination of paclitaxel administered on a weekly schedule in combination with bevacizumab administered every two weeks can induce response rates as high as 70% (8, 9). It should be noted that this combination was tested using a study group that include women with both platinum-sensitive and resistant ovarian cancer recurrences. Nonetheless, this observation is significant because response rates for most single agent regimens against platinum-resistant ovarian cancer range from 12-30% (1-7). Because nearly all agents used to treat ovarian cancer ultimately fall in their ability to arrest or reverse disease progression. Survival for women with platinum resistant ovarian cancer is 12-24 months.
The present invention addresses these issues and provides a solution for a long-felt need in the art to provide effective ovarian cancer treatment.